ClinVar Genomic variation as it relates to human health

The p.Leu221PhefsX25 variant in BBS2 has been reported in 1 homozygous and 2 compound heterozygous individuals with Bardet-Biedl syndrome (BBS; Hjortshøj 2010). This variant has been identified in 0.03% (2/6592) of European (Finnish) chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 221 and leads to a premature termination codon 25 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Complete loss of BBS2 function is an established disease mechanism in BBS. In summary, this variant meets our criteria to be classified as pathogenic for BBS in an autosomal recessive manner.

Variant summary: BBS2 c.661delC (p.Leu221PhefsX25) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 251270 control chromosomes (gnomAD). c.661delC has been reported in the literature in both homozygous and compound heterozygous individuals affected with Bardet-Biedl Syndrome (Hjortshoj_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and five classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Leu221Phefs*25) in the BBS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252, 20177705, 24608809, 26518167). This variant is present in population databases (rs770258677, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Bardet-Biedl syndrome (PMID: 20120035). ClinVar contains an entry for this variant (Variation ID: 208564). For these reasons, this variant has been classified as Pathogenic.

The c.661delC (p.L221Ffs*25) alteration, located in exon 6 (coding exon 6) of the BBS2 gene, consists of a deletion of one nucleotide at position 661, causing a translational frameshift with a predicted alternate stop codon after 25 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the BBS2 c.661delC alteration has an overall frequency of <0.01% (7/282674) total alleles studied. The highest observed frequency was 0.02% (5/25080) of European (Finnish) alleles. This pathogenic alteration has been reported in multiple unrelated individuals with Bardet-Biedl syndrome (BBS) in the homozygous state or in conjunction with a second pathogenic BBS2 allele (Hjortsh&oslash;j, 2010). Based on the available evidence, this alteration is classified as pathogenic.